Cyclin dependent kinase inhibitor p21Cip1 Waf1 is a key protein participating in cell cycle regulation. Previous studies have shown that HDACi selleck chem inhibitor activates expression of p21Cip1 Waf1 through enhanced histone acetylation around the p21Cip1 Waf1 promoter. We performed western blot analysis with treated and control Panc 1 cells to clar ify the effect of belinostat on p21Cip1 Waf1 expression. Beli nostat induced an upregulation of p21Cip1 Waf1, as has been described for other HDAC inhibitors in pancreatic cancer. Increased expression of p21Cip1 Waf1 in these studies was associated with normalization of the cell cycle and induction of apoptosis. Regarding the effect of belinostat in vivo, we observed that belinostat was an effective growth inhibitor of T3M4 pancreatic cancer cells in a nude mouse model.
Mice treated with belinostat showed xenograft growth inhibition for more than 28 days after tumour inocula tion, without any signs of toxicity. The reduction in the tumour volume was associated with decreased cell pro liferation, as shown by Ki 67 immunohistochemistry. Similar observations in in vivo tumour models were shown in previous studies, e. g. in human ovarian cancer s. c. xenografts. the efficacy of the treatment with belino stat was further enhanced when a combination therapy with carboplatin was added. Plumb et al. described a significant dose dependent growth delay of human colon tumour xenografts in mice after belinostat treatment, without signs of toxicity. In contrast to our in vitro observations, we could not find an additional effect of combined therapy with beli nostat and gemcitabine in vivo.
A possible explanation for this discrepancy is the relatively high dosage of gem citabine administered in the in vivo study. This might have covered a possible additional belinostat effect. Conclusion In summary, this preclinical study using in vitro and in vivo pancreatic cancer models shows that belinostat is effective as a monotherapy of pancreatic cancer, primarily by inhibition of proliferation and induction of apoptosis. In vitro results revealed that belinostat can be successfully combined with gemcitabine to potentiate induction of apoptosis in the tumour cells. These findings should be confirmed in the clinical setting in PDAC patients.
Background Hepatocellular carcinoma is the most common primary tumor of the liver and represents an unmet medical need, being among the most common tumor diseases and causes of cancer related deaths worldwide and showing a rising incidence also in Western countries. Although the multi kinase inhibitor sorafenib has recently been approved for treatment Carfilzomib of advanced stage HCC, the overall efficacy still remains dissatisfying. Besides genetic alterations, changes in chromatin have recently been identified to contribute to tumorigenesis.